Prostaglandins and the derivatives thereof have various biological actions, such as a vasodilating action, a prophlogistic action, an inhibitory action of blood platelet aggregation, a uterine muscle contraction action, an intestine contraction action and a lowering action of intraocular pressure, and can be used in the preparation of medicaments for treatment or prevention of myocardial infarction, angina pectoris, arteriosclerosis, hypertension, or duodenal ulcer, which are valuable for human as well as veterinary applications.
For the last few decades, many academic researchers and industrial organizations have made tremendous efforts in exploring various key intermediates as well as innovative processes for efficient and cost-saving synthesis of Prostaglandins (Collines, P. W. et. al., 1993, Chem. Rev. 93, 1533).
Specifically, lactones of Formula I are very important late-stage intermediates for synthesis of Prostaglandin 2α compounds.
                I-1:  being a double bond,                    X1 and X2 being protecting group                        I-2:  being double bond,                    X1 and X2 being H                        I-3:  being single bond,                    X1 and X2 being protecting group or H                        
For example, Lactones of Formula I-1 or I-2, wherein R2 is methylene and R3 is n-butyl, are key intermediates for the synthesis of nature Prostaglandin F2α, E2 and I2, as reported in E. J. Corey, et al, J. Am. Chem. Soc. 1970, 92, 397; and J. Am. Chem. Soc. 1977, 99, 2006.
Lactones of Formula I-1 or I-2, wherein R2 is methylene and R3 is benzyl, are advanced intermediates for the synthesis of Bimatoprost, as disclosed in USP 2005/0209337.
Lactones of Formula I-1 or I-2, wherein R2 is —CH2O— and R3 is a substituted phenyl, are intermediates for the synthesis of (+)-Cloprostenol, Travoprost and (+)-Fluprostenol, as disclosed in EP 0362686 and USP 2005/0209337.
Lactones of Formula I-3, wherein R2 is methylene and R3 is benzyl, are intermediates for the synthesis of Latanoprost, as disclosed in U.S. Pat. No. 5,359,095.
In industry, the above mentioned Lactones of Formula I have been prepared from a famous intermediate III (the so-called Corey aldehyde) via the route depicted below in Scheme 1:
wherein P is a protecting group; and R2 and R3 are as defined above.
The synthesis of Corey aldehyde III (Corey's process) consists of more than 12 reaction steps in a linear route with the use of cyclopentadiene as the starting material. In Corey's process, not only is it difficult to proceed with the production reproducibly but the final target compound is usually obtained in a low yield. In addition, the major drawback of the Corey's process is associated with the poor selectivity toward the reduction of the 15-ketone functional group on the ω-side chain (Scheme 1), which often results in a considerable amount of the 15-β isomer generated as a major impurity. [See Corey, et. al., 1987, J. Am. Chem. Soc., 109, 7925; Corey, et. al., 1972, J. Am. Chem. Soc., 94, 8616; Corey, et. al., 1971, J. Am. Chem. Soc., 93, 1491; and Noyori, et. al., 1979, J. Am. Chem. Soc., 101, 5843]. In order to remove the 15-β isomer, it is necessary to utilize chromatography in the Corey's process for the separation of the isomers having slight differences in the Rf values.
Given the above, conventional approaches for producing Lactones of Formula I encountered problems to be solved. The objective of the invention is to provide a simpler as well as a cost-effective synthesis route for Lactones of Formula I to eliminate the problems associated with the conventional processes, either in the aspect of a number of synthetic steps or in the necessity of removing unwanted isomers.